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Chemical Compound Review

Piritrexim     9-[(2,5- dimethoxyphenyl)methyl]-10- methyl...

Synonyms: Piritrexima, Piritrexime, Piritreximum, CHEMBL7492, SureCN8124, ...
 
 
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Disease relevance of PIRITREXIM ISETHIONATE

 

High impact information on PIRITREXIM ISETHIONATE

  • Absolute bioavailability in two patients who were also monitored following a single i.v. dose of 140 and 200 mg/m2/day of piritrexim was 35 and 93%, respectively [6].
  • In contrast, although Pyr- and Tmp-resistant cells expressed parental levels of wild type DHFR, they displayed a high degree of resistance to DAP and, surprisingly, to the lipophilic MTX analogs piritrexim (PTX) and trimetrexate (TMTX), while maintaining sensitivity to MTX [7].
  • Upon further selection with piritrexim, resistant variants emerge with amplified dihydrofolate reductase but not with multidrug resistance genes [8].
  • A Chinese hamster cell line harboring the L22F mutant also demonstrated an increased sensitivity of piritrexim relative to antifolates [9].
  • Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain [10].
 

Chemical compound and disease context of PIRITREXIM ISETHIONATE

 

Biological context of PIRITREXIM ISETHIONATE

  • 2,4-Diamino-6-[(3',4'-dichloro-N-methylanilino)methyl]pyrido[3, 2-d]pyrimidine (10) had an IC50 of 0.022 microM against P. carinii DHFR and was comparable in potency to TMQ and PTX [15].
  • Competitive protein binding assay for piritrexim [16].
  • We have examined the ability of various modulators of the MDR phenotype to sensitize T19 cells to TMTX and PTX in a clonogenic assay [17].
  • QSAR studies on biological activity of piritrexim analogues against pc DHFR [18].
  • The number of renal-impaired patients enrolled was too small to establish a maximum tolerated dose for this group (piritrexim became unavailable), but the combination was tolerated in the patients with impaired renal dysfunction [14].
 

Anatomical context of PIRITREXIM ISETHIONATE

 

Associations of PIRITREXIM ISETHIONATE with other chemical compounds

  • Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 microM) with 14 compounds below 0.1 microM, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 microM) [22].
  • Sucrose density gradient centrifugation of partially purified amido PRTase showed three molecular forms of the enzyme: an inactive tetramer (10.2 S) formed in the presence of AMP, an active dimer (6.7 S) formed with P-Rib-PP, and an inactive dimer (7.2 S) with piritrexim [23].
  • Leucovorin, a reduced folate that can bypass the inhibition of DHFR by antifols in mammalian cells but not in protozoa, did not affect the ability of piritrexim to inhibit T. gondii replication [19].
  • O-Demethylation and subsequent conjugation were the main pathways of metabolism; the demethyl metabolites of piritrexim were potent inhibitors of dihydrofolate reductase and were cytotoxic to cells in culture [24].
  • The maximum tolerated dose was thought to be piritrexim 25 mg orally three times daily (days 1-4), paclitaxel 150 to 175 mg/m2 (days 1, 15), and gemcitabine 1,000 mg/m2 (days 1, 15) [25].
 

Gene context of PIRITREXIM ISETHIONATE

  • These results support the idea that removal of the 5-methyl group of piritrexim along with restriction of tau(1) and tau(2) can translate into selectivity for DHFR from pathogens [26].
  • In contrast to known lipophilic inhibitors of DHFR such as trimetrexate and piritrexim, members of this series of pyrroloquinazolines were not susceptible to P-glycoprotein-mediated multidrug resistance and also showed significant distribution into lung and brain tissue [27].
  • Rather, a pathway appears to exist that protects T19 MDR cells from the cytotoxicity of PTX without requiring a P-170 function [17].
  • In December 1996, ILEX formed a joint venture with MPI Enterprises for the manufacture and marketing of piritrexim [28].
  • We have observed that 25 microM MTX or piritrexim, a "non-classical" antifolate, induce several-fold accumulations of AICAR and N-succino-AICAR to a combined cellular concentration of 89 microM in mouse L1210 leukemia cells after 2 h [29].
 

Analytical, diagnostic and therapeutic context of PIRITREXIM ISETHIONATE

  • Phase I trial of piritrexim capsules using prolonged, low-dose oral administration for the treatment of advanced malignancies [30].
  • Therapeutic drug monitoring may thus play an important role in adjusting the dose and schedule of piritrexim in future trials [1].
  • This compound is over 10(3)-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials [22].
  • Twenty-four patients of which sixteen had received prior chemotherapy, were initially treated with 25 mg piritrexim orally administered trice daily for four days, repeated weekly, with provision for dose escalation or reduction according to observed toxicity [5].
  • Molecularly imprinted microspheres were synthesised using the antitumor drug piritrexim (PTX) as a template molecule by aqueous microsuspension polymerisation and were used as a high-performance liquid chromatographic stationary phase [31].

References

  1. Pediatric phase I trial, pharmacokinetic study, and limited sampling strategy for piritrexim administered on a low-dose, intermittent schedule. Adamson, P.C., Balis, F.M., Miser, J., Arndt, C., Wells, R.J., Gillespie, A., Aronson, L., Penta, J.S., Clendeninn, N.J., Poplack, D.G. Cancer Res. (1992) [Pubmed]
  2. Phase II trial of piritrexim in metastatic melanoma using intermittent, low-dose administration. Feun, L.G., Gonzalez, R., Savaraj, N., Hanlon, J., Collier, M., Robinson, W.A., Clendeninn, N.J. J. Clin. Oncol. (1991) [Pubmed]
  3. Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: marked improvement in potency relative to trimethoprim and species selectivity relative to piritrexim. Rosowsky, A., Forsch, R.A., Queener, S.F. J. Med. Chem. (2002) [Pubmed]
  4. 2,4-Diaminothieno[2,3-d]pyrimidine analogues of trimetrexate and piritrexim as potential inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. Rosowsky, A., Mota, C.E., Wright, J.E., Freisheim, J.H., Heusner, J.J., McCormack, J.J., Queener, S.F. J. Med. Chem. (1993) [Pubmed]
  5. A phase II and pharmacokinetic study with oral piritrexim for metastatic breast cancer. de Vries, E.G., Gietema, J.A., Workman, P., Scott, J.E., Crawshaw, A., Dobbs, H.J., Dennis, I., Mulder, N.H., Sleijfer, D.T., Willemse, P.H. Br. J. Cancer (1993) [Pubmed]
  6. Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule. Adamson, P.C., Balis, F.M., Miser, J., Wells, R.J., Bleyer, W.A., Williams, T.E., Gillespie, A., Penta, J.S., Clendeninn, N.J., Poplack, D.G. Cancer Res. (1990) [Pubmed]
  7. Characterization of a lipophilic antifolate resistance provoked by treatment of mammalian cells with the antiparasitic agent pyrimethamine. Assaraf, Y.G., Slotky, J.I. J. Biol. Chem. (1993) [Pubmed]
  8. Sequential amplification of dihydrofolate reductase and multidrug resistance genes in Chinese hamster ovary cells selected for stepwise resistance to the lipid-soluble antifolate trimetrexate. Assaraf, Y.G., Molina, A., Schimke, R.T. J. Biol. Chem. (1989) [Pubmed]
  9. Variants of human dihydrofolate reductase with substitutions at leucine-22: effect on catalytic and inhibitor binding properties. Ercikan-Abali, E.A., Waltham, M.C., Dicker, A.P., Schweitzer, B.I., Gritsman, H., Banerjee, D., Bertino, J.R. Mol. Pharmacol. (1996) [Pubmed]
  10. Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain. Chan, D.C., Fu, H., Forsch, R.A., Queener, S.F., Rosowsky, A. J. Med. Chem. (2005) [Pubmed]
  11. Drug concentration-dependent DNA lesions are induced by the lipid-soluble antifolate, piritrexim (BW301U). Richards, R.G., Brown, O.E., Gillison, M.L., Sedwick, W.D. Mol. Pharmacol. (1986) [Pubmed]
  12. Neoadjuvant PFL augmented by methotrexate and piritrexim followed by concomitant chemoradiotherapy for advanced head and neck cancer: a feasible and active approach. Vokes, E.E., Haraf, D.J., McEvilly, J.M., Mick, R., Kozloff, M.F., Goldman, M.D., Moran, W.J., Clendeninn, N.J., Collier, M.A., Weichselbaum, R.R. Ann. Oncol. (1992) [Pubmed]
  13. Treatment of psoriasis with piritrexim, a lipid-soluble folate antagonist. Guzzo, C., Benik, K., Lazarus, G., Johnson, J., Weinstein, G. Archives of dermatology. (1991) [Pubmed]
  14. Phase I study of piritrexim and gemcitabine in patients with advanced solid tumors. Huie, M., Carducci, M., Liu, G., Wilding, G., Marnocha, R., Izquierda, M., Thomas, J. Am. J. Clin. Oncol. (2005) [Pubmed]
  15. 2,4-Diaminopyrido[3,2-d]pyrimidine inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii. Rosowsky, A., Forsch, R.A., Queener, S.F. J. Med. Chem. (1995) [Pubmed]
  16. Competitive protein binding assay for piritrexim. Woolley, J.L., Ringstad, J.L., Sigel, C.W. Journal of pharmaceutical sciences. (1989) [Pubmed]
  17. Differential reversal of lipophilic antifolate resistance in mammalian cells with modulators of the multidrug resistance phenotype. Assaraf, Y.G., Borgnia, M.J. Anticancer Drugs (1993) [Pubmed]
  18. QSAR studies on biological activity of piritrexim analogues against pc DHFR. Agrawal, V.K., Sohgaura, R., Khadikar, P.V. Bioorg. Med. Chem. (2002) [Pubmed]
  19. Potent antipneumocystis and antitoxoplasma activities of piritrexim, a lipid-soluble antifolate. Kovacs, J.A., Allegra, C.J., Swan, J.C., Drake, J.C., Parrillo, J.E., Chabner, B.A., Masur, H. Antimicrob. Agents Chemother. (1988) [Pubmed]
  20. In vitro and in vivo immunomodulatory effects of anti-Pneumocystis carinii drugs. Viora, M., De Luca, A., D'Ambrosio, A., Antinori, A., Ortona, E. Antimicrob. Agents Chemother. (1996) [Pubmed]
  21. Piritrexim in advanced, refractory carcinoma of the urothelium (E3896): a phase II trial of the Eastern Cooperative Oncology Group. Roth, B.J., Manola, J., Dreicer, R., Graham, D., Wilding, G. Investigational new drugs. (2002) [Pubmed]
  22. Lipophilic antifolates as agents against opportunistic infections. 1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii and Pneumocystis carinii in in vitro evaluations. Piper, J.R., Johnson, C.A., Krauth, C.A., Carter, R.L., Hosmer, C.A., Queener, S.F., Borotz, S.E., Pfefferkorn, E.R. J. Med. Chem. (1996) [Pubmed]
  23. Mechanisms of inhibition of amido phosphoribosyltransferase from mouse L1210 leukemia cells. Schoettle, S.L., Crisp, L.B., Szabados, E., Christopherson, R.I. Biochemistry (1997) [Pubmed]
  24. The disposition and metabolism of [14C]piritrexim in rats after intravenous and oral administration. Woolley, J.L., Deangelis, D.V., Crouch, R.C., Shockcor, J.P., Sigel, C.W. Drug Metab. Dispos. (1991) [Pubmed]
  25. Gemcitabine, Paclitaxel, and piritrexim: a phase I study. Liu, G., Bailey, H.H., Arzoomanian, R.Z., Alberti, D., Binger, K., Volkman, J., Feierabend, C., Marnocha, R., Wilding, G., Thomas, J.P. Am. J. Clin. Oncol. (2003) [Pubmed]
  26. Synthesis of classical and nonclassical, partially restricted, linear, tricyclic 5-deaza antifolates. Gangjee, A., Zeng, Y., McGuire, J.J., Kisliuk, R.L. J. Med. Chem. (2002) [Pubmed]
  27. High-affinity inhibitors of dihydrofolate reductase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size. Kuyper, L.F., Baccanari, D.P., Jones, M.L., Hunter, R.N., Tansik, R.L., Joyner, S.S., Boytos, C.M., Rudolph, S.K., Knick, V., Wilson, H.R., Caddell, J.M., Friedman, H.S., Comley, J.C., Stables, J.N. J. Med. Chem. (1996) [Pubmed]
  28. Piritrexim (ILEX Oncology). Fraser, J.A., Bartlett, J. IDrugs : the investigational drugs journal. (1999) [Pubmed]
  29. Antifolates induce primary inhibition of the de novo purine pathway prior to 5-aminoimidazole-4-carboxamide ribotide transformylase in leukemia cells. Lyons, S.D., Christopherson, R.I. Biochem. Int. (1991) [Pubmed]
  30. Phase I trial of piritrexim capsules using prolonged, low-dose oral administration for the treatment of advanced malignancies. Feun, L.G., Savaraj, N., Benedetto, P., Hanlon, J., Sridhar, K.S., Collier, M., Richman, S., Liao, S.H., Clendeninn, N.J. J. Natl. Cancer Inst. (1991) [Pubmed]
  31. Separation and determination of the antitumor drug piritrexim by molecularly imprinted microspheres in high-performance liquid chromatography. Lai, J.P., He, X.W., Chen, F. Analytical and bioanalytical chemistry. (2003) [Pubmed]
 
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